Identification, Validation, and Manipulation of Neural Circuits Related to Mental Illness, in Non-human Primates

Presenter:

Douglas L. Meinecke, Ph.D.
Division of Translational Research

Goal:

The goal of this initiative is to support the identification, validation and manipulation of neural circuits that underlie cognitive, emotional, and social processes impacted in mental illnesses. The initiative is focused on probing psychiatrically relevant behavior through studies in non-human primates. This initiative is intended to complement existing NIMH-funded preclinical investigation of circuits which have often focused on smaller brains.

Rationale:

The use of circuit- and cell-type-specific strategies for manipulation and monitoring of neural circuits has proven successful in elucidating the neural mechanisms underlying aspects of cognitive function, affect regulation, and social processes in rodents. These experiments have often been motivated by a desire to translate these insights from experimental systems to the mechanisms of psychopathology and advance new therapies in humans. Rodent model systems have played a considerable role in these experimental paradigms. Although these models are of continuing value in understanding brain mechanisms relevant to mental health and disability, vast differences in brain structure and the inability to model many aspects of human cognition and affect highlights their translational limits. Non-human primate models are an intermediate but integral step between rodents and humans to identifying and characterizing homologous circuits across species. Confirmation of homology in humans, combined with the expanding technical repertoire to manipulate neural circuitry should advance the translational goal of clinically actionable interventions.

The validation of homology between animal and human neural circuits and psychiatrically relevant behaviors includes multiple levels of comparison, many of which are supported by complementary NIH initiatives. These initiatives encourage the use and development of comparative gene transcription and regulation, as well as anatomical, physiological and effective modulation/intervention strategies. For example, the BRAIN Initiative Cell Census data for mouse, marmoset, and human enable comparative studies at the level of cell-type gene expression, morphology, and connectivity. Validation of evolutionarily conserved processes (homology) will inform concurrent NIMH initiatives focused on the therapeutic development pipeline from animals to humans.

This initiative seeks also to address a gap in on-going announcements on the reverse translation of human to animal models. Bi-directional translation and validation would be an important part of mechanism testing. Specifically, human data from multiple modalities (i.e., computational modeling, neuroimaging, electrophysiology) can identify candidate psychiatrically relevant circuits with reverse translation to non-human primate studies for mechanistic testing. The non-human primate intermediate can simultaneously be used to test and advance circuit manipulation techniques established in rodent models in the context of human relevant behaviors.